High-risk human papillomaviruses (HPVs) are etiological agents of cervical cancer, the second most common cause of cancer death in women worldwide and are also associated with a number of other anogenital tract carcinomas, including, anal, vulvar and penile cancers as well as approximately 20% of oral cancers, particularly oropharyngeal carcinomas. Due to the long latency period between the initial HPV infection and cancer development, It will be decades, however, before a recently introduced prophylactic vaccine that is to prevent new infections by the two most common high-risk HPVs will have a significant impact on the incidence and mortality of HPV associated cancers. Till then, 10 women will die of HPV associated cervical cancer every day in the US, alone. HPV-associated carcinogenesis is driven by viral E6/E7 oncoprotein expression; these proteins not only contribute to induction of premalignant lesions, but also mechanistically contribute to malignant progression. We have shown that the HPV E7 oncoprotein causes epigenetic reprogramming of HPV infected cells by causing a dramatic decrease in trimethylation of lysine residue 27 of histone H3. Since lysine 27 trimethylation of histone H3 marks silenced chromatin, erasing this mark causes increased expression of genes that are normally silenced in epithelial cells. Such genes include the tumor suppressor and cervical cancer biomarker p16INK4A, as well as many homeobox genes that are critical for cell fate determination and organismal development. This project is focused on investigating mechanisms and biological consequences of HPV16 E7 induced epigenetic reprogramming. Aim 1 is to determine the mechanism by which HPV16 E7 expression causes increased expression of the two enzymes, JMJD3 and UTX, which remove the repressive trimethyl mark on lysine 27 of histone H3. Aim 2 is to determine the biological consequences of increased JMMJD3 and UTX expression in HPV expressing epithelial cells. Aim 3 is to determine the biological consequences of E7 mediated disruption of E2F6 containing polycomb repressive complexes and increased expression of the histone methyl transferase and oncoprotein, EZH2, in HPV16 E7 expressing epithelial cells. Since, in contrast to somatic mutations, epigenetic reprogramming is potentially reversible by small molecule inhibitors of the corresponding histone modifying enzymes, these studies may have therapeutic implications for HPV-associated lesions and cancers.